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Contains fulltext : 232930.pdf (Publisher’s version ) (Closed access) BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to

The legal professionals of lawfare in Latin America use the Italian process of mani pulite as an example to justify their intervention in the institutional life of their countries. Nevertheless, the differences between them unveil the true nature of lawfare: the persecution of opponents to reconfigure the domestic political map. Los operadores judiciales del lawfare en América Latina toman como ejemplo el proceso de mani pulite para justificar su intervención en la vida institucional de sus países. Sin embargo, las diferencias entre ambos develan la verdadera naturaleza del lawfare: la persecución de opositores tendiente a redefinir el mapa político interno. Gli operatori giudiziari del lawfare per giustificare gli interventi nella vita istituzionale dei latinoamericani utilizzano come esempio da seguire le modalità di indagine utilizzate da mani pulite. Tuttavia, alcune differenze con l’Italia rivelano la vera natura del lawfare: la persecuzione di oppositori allo scopo di ridisegnare la mappa politica interna.

Background On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. Methods In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a $25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to,1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). Results During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. Conclusions Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints. Copyright © 2021 by the American Society of Nephrology.

The Aguada Pichana Gas field is located in the center of the prolific Neuquén Basin, in Argentina. It produces gas and condensate through monobore completions. Since 2006, an increase in liquid loading has become an issue in current wells conditions, resulting in the need of reducing production tubing size to enable stable gas production for continuous liquid removal. Following analysis, the appropriate solution resulted in running a velocity string (VS) as an effective means for liquid removal at current and future production conditions. The challenge was to find a hanger system, which would allow, without killing the well, to hang a 2.0-in[CSH1] CT VS. Additionally, the hanger should facilitate unloading the well by circulating nitrogen and restore the production rate without the need to recover the VS. After a field trial, the first phase of the campaign has been completed with the introducion of a special designed fluted seal and retrievable CT VS hanger system (quantity: 20 jobs), and second phase of campaign (quantity: 60 jobs) with a low cost and locally manufactured reliable system. The paper describes the operational planning, different hanger systems, deployment methods and lessons learned after more than 80 jobs.

A field study was established to evaluate symptoms, growth, yield, and nut quality of walnut trees subjected to multiple exposures of simulated bispyribac-sodium drift. Nut yield the year following simulated drift treatment was also evaluated because tissue differentiation for future fruiting position occurs in the prior season. Bispyribac-sodium was applied four times, at weekly intervals, at 0.5% and 3% of the use rate in rice (45 g ai ha-1). Injury from the 0.5% rate exceeded 5% after three applications. In general, the severity of the symptoms peaked 14 d after last application (23% and 40% injury for 0.5% and 3% rate, respectively) and subsequently remained nearly constant over the duration of the study. Growth of shoots treated with the 0.5% rate was initially delayed during the treatment regime but recovered after treatments ended; however, walnut shoots exposed to the higher rate had fewer internodes than nontreated trees at the end of the season. No measurable reduction in walnut yield or average nut weight either in the year of exposure or in the subsequent year was observed. However, both rates negatively affected walnut kernel color in the year of exposure.Nomenclature: Bispyribac-sodium; rice, Oryza sativa L.; walnut, Juglans regia L.

A field study was established to study symptoms, growth and yield of 2-year-old walnut trees exposure to simulated drift of several herbicides commonly used in rice production. Bispyribac-sodium, bensulfuron-methyl, and propanil were applied at four rates representing 0.5%, 1%, 3% and 10% of the normal use rate in rice (45, 70, and 6725 g ai ha-1, for the three herbicides respectively). Symptoms started to appear approximately 7 days after application (DAT) and peaked 28 DAT. At that time, bispyribac-sodium caused greater injury at low drift rates (6% and 15% visual injury for 0.5% and 1% rate, respectively) compared to bensulfuronmethyl and propanil. Bispyribac-sodium also appeared to slow walnut shoot elongation compared to nontreated trees; however, no yield reductions were observed either in the year after drift exposure. The effect of bispyribac-sodium simulated drift on the yield and nut quality in the year of drift exposure was evaluated in a separate study on 3-year-old walnut trees. While no yield or nut quality reductions were observed, a linear correlation between rate of bispyribac-sodium and color, an important quality factor, was found: higher herbicide rates tended to be associated with darker kernel color. Bispyribac-sodium may damage nearby walnut orchards if drifted at significant amounts. However, it is unlikely that in a field situation bispyribac-sodium would drift at high enough levels to cause the symptoms observed from the 10% use rates in this study.Nomenclature: bispyribac-sodium; bensulfuron-methyl; propanil; rice, Oryza sativa L.; walnut, Juglans regia L.

Inhibiting MYC has long been considered unfeasible, although its key role in human cancers makes it a desirable target for therapeutic intervention. One reason for its perceived undruggability was the fear of catastrophic side effects in normal tissues. However, we previously designed a dominant-negative form of MYC called Omomyc and used its conditional transgenic expression to inhibit MYC function both in vitro and in vivo. MYC inhibition by Omomyc exerted a potent therapeutic impact in various mouse models of cancer, causing only mild, well-tolerated, and reversible side effects. Nevertheless, Omomyc has been so far considered only a proof of principle. In contrast with that preconceived notion, here, we show that the purified Omomyc mini-protein itself spontaneously penetrates into cancer cells and effectively interferes with MYC transcriptional activity therein. Efficacy of the Omomyc mini-protein in various experimental models of non-small cell lung cancer harboring different oncogenic mutation profiles establishes its therapeutic potential after both direct tissue delivery and systemic administration, providing evidence that the Omomyc mini-protein is an effective MYC inhibitor worthy of clinical development.

Background: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies. © 2018 The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Background The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. Results All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). Conclusion We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

ImportanceAlthough IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, there is no validated tool to predict disease progression. This limits patient-specific risk stratification and treatment decisions, clinical trial recruitment, and biomarker validation. ObjectiveTo derive and externally validate a prediction model for disease progression in IgAN that can be applied at the time of kidney biopsy in multiple ethnic groups worldwide. Design, Setting, and ParticipantsWe derived and externally validated a prediction model using clinical and histologic risk factors that are readily available in clinical practice. Large, multi-ethnic cohorts of adults with biopsy-proven IgAN were included from Europe, North America, China, and Japan. Main Outcomes and MeasuresCox proportional hazards models were used to analyze the risk of a 50% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease, and were evaluated using the R-D(2) measure, Akaike information criterion (AIC), C statistic, continuous net reclassification improvement (NRI), integrated discrimination improvement (IDI), and calibration plots. ResultsThe study included 3927 patients; mean age, 35.4 (interquartile range, 28.0-45.4) years; and 2173 (55.3%) were men. The following prediction models were created in a derivation cohort of 2781 patients: a clinical model that included eGFR, blood pressure, and proteinuria at biopsy; and 2 full models that also contained the MEST histologic score, age, medication use, and either racial/ethnic characteristics (white, Japanese, or Chinese) or no racial/ethnic characteristics, to allow application in other ethnic groups. Compared with the clinical model, the full models with and without race/ethnicity had better R-D(2) (26.3% and 25.3%, respectively, vs 20.3%) and AIC (6338 and 6379, respectively, vs 6485), significant increases in C statistic from 0.78 to 0.82 and 0.81, respectively (Delta C, 0.04; 95% CI, 0.03-0.04 and Delta C, 0.03; 95% CI, 0.02-0.03, respectively), and significant improvement in reclassification as assessed by the NRI (0.18; 95% CI, 0.07-0.29 and 0.51; 95% CI, 0.39-0.62, respectively) and IDI (0.07; 95% CI, 0.06-0.08 and 0.06; 95% CI, 0.05-0.06, respectively). External validation was performed in a cohort of 1146 patients. For both full models, the C statistics (0.82; 95% CI, 0.81-0.83 with race/ethnicity; 0.81; 95% CI, 0.80-0.82 without race/ethnicity) and R-D(2) (both 35.3%) were similar or better than in the validation cohort, with excellent calibration. Conclusions and RelevanceIn this study, the 2 full prediction models were shown to be accurate and validated methods for predicting disease progression and patient risk stratification in IgAN in multi-ethnic cohorts, with additional applications to clinical trial design and biomarker research.

Breast cancer is a leading cause of cancer mortality in women due to the high frequency of metastatic disease, which, despite advances in therapeutic options, is still essentially incurable. The role of Myc in promoting tumorigenesis is beyond doubt, but there are contradictory reports in the literature on its role in the metastatic process. Using a Myc dominant negative termed Omomyc, we have demonstrated in various mouse models that Myc inhibition is a safe and effective therapeutic approach against several types of cancer, regardless of the tissue of origin or the driver oncogenic lesion. So far, Omomyc has only been tested in primary tumors. However, since many steps of the metastatic cascade have been reported to depend on Myc, we hypothesized that Omomyc could be extremely effective in both the prevention and treatment of metastasis too. Here we show that Omomyc expression has a dramatic effect on colony formation capacity in human breast cancer cell lines representative of all the molecular subtypes of the disease. In MDA-MB-231 cells, not only did it impair their proliferation but also migration, invasion and their capacity to induce angiogenesis, key aspects of the metastatic process. We demonstrate that, in vivo, Omomyc reduces the growth of orthotopically-implanted human breast cancer cells in immunocompromised mice, induces regression of established metastases after primary tumor resection and impairs the development of lung metastases after tail vein injection. In the immunocompetent MMTV-PyMT transgenic model, Omomyc expression dramatically delays the formation and growth of mammary fat pad tumors, thereby preventing the appearance of lung metastases. When the purified Omomyc mini-protein is administered exogenously, we observe remarkable growth inhibition in vitro that recapitulates transgenic expression of Omomyc. Intravenous administration of the mini-protein reduces lung colonization and tumor growth in vivo. We have demonstrated for the first time the applicability of Omomyc against metastasis, challenging the pre-established notion that Myc inhibition could potentiate, rather than inhibit, invasion. Finally, we have validated the use of the purified Omomyc mini-protein as the first directly-deliverable Omomyc-based drug for the treatment of metastatic breast cancer, providing a new therapeutic opportunity for patients suffering from this dreadful and incurable disease. Citation Format: Daniel Massó-Vallés, Marie-Eve Beaulieu, Toni Jauset, Erika Serrano, Sandra Martínez-Martín, Laia Foradada, Virginia Castillo, Francisco Castillo, Génesis Martín, Sílvia Casacuberta-Serra, Mariano F. Zacarias-Fluck, Antonio Luque-García, Marta Escorihuela, Jonathan R. Whitfield, Joaquín Arribas, Laura Soucek. Translating Myc inhibition to the clinic in metastatic breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1823.